Mammalian Neurogenetics

The Mammalian Neurogenetics Group, led by Professor Elizabeth Fisher, is studying the genetic causes of neuronal dysfunction and degeneration, in two main areas, motor neuron degeneration and Down syndrome.

Motor neuron diseases are cruel and untreatable killers that can strike at any age. One in every 400 people in UK who die have some form of motor neuron disease. We know that certain genes either cause or contribute to the motor neuron diseases, but, we do not how these genes work, or what most of them are. In this project, run by Dr Anny Devoy, we are creating new mouse models with the same mutations that cause motor neuron disease (amyotrophic lateral sclerosis, ALS) in humans, specifically in the FUS gene. These models are ‘knock in’ mice and therefore produce the mutant protein at physiological levels. We work with a range of collaborators who have specialist expertise in the study of nerve and muscle to help us understand the effects of the genes we are interested in. We are doing this to provide new information about the disease, and, ultimately, help with treatments and, eventually, a cure.

Working with this, and existing models, and with human patient samples, we are also undertaking novel approaches to dissect the alterations in RNA metabolism that may results from mutations in ‘ALS’ genes. In this project, run by Dr Pietro Fratta who is a key collaborator of ours, working within the Sobel Department of Motor Neuroscience at the UCL Institute of Neurology, we are particularly interested in local translation in different sub-cellular regions of the motor neuron.

Analysing models of Down syndrome to understand dementia and other facets of the disorder

Down syndrome is the single most common genetic form of cognitive disability, and affects many other tissues in addition to the brain. We know that it is caused by having an extra copy of chromosome 21, but we do not know why this has such a profound effect on the individual. We (Professor Fisher’s group and that of Dr Victor Tybulewicz of the Francis Crick Institute) have created a model of Down syndrome to try to identify which genes cause the various parts of the syndrome and affect different tissues. In a project run by Dr Frances Wiseman, we are particularly interested in the greatly increased propensity to develop Alzheimer disease in Down syndrome, and are undertaking genetic, molecular and cellular approaches to dissect the pathways of neurodegeneration. We work with a large number of collaborators with specialist expertise in heart development, behaviour, electrophysiology (of interest because of the increase of epilepsy in Down syndrome), brain development, to try to understand the interplay of genes and the various features of Down syndrome. By doing this we hope to help with aspects of the syndrome, such as the neurological effects. We are also a constituent laboratory of the Welcome Trust funded LonDowns consortium.

Creating new mouse models of Neurodegeneration

We are undertaking two further projects in the lab to genome engineer new mouse models of dystonia, with Dr Fei Zhu, and a new mouse model of motor neuron degeneration, with Ms Francesca De Giorgio in collaboration with Dr Anny Devoy and Dr Abraham Acevedo of the University of Tenerife. We also work closely with the laboratory of Dr Adrian Isaacs including with Dr Carmelo Milioto to create a new model with C9orf72 gene mutations.